Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas

• Published in: Cell reports. Medicine 2023-06, Vol.4 (6), p.101082, Article 101082
• Main Authors: Bredel, Markus, Espinosa, Lluís, Kim, Hyunsoo, Scholtens, Denise M., McElroy, Joseph P., Rajbhandari, Rajani, Meng, Wei, Kollmeyer, Thomas M., Malta, Tathiane M., Quezada, Michael A., Harsh, Griffith R., Lobo-Jarne, Teresa, Solé, Laura, Merati, Aran, Nagaraja, Surya, Nair, Sindhu, White, Jaclyn J., Thudi, Nanda K., Fleming, Jessica L., Webb, Amy, Natsume, Atsushi, Ogawa, Seishi, Weber, Ruthild G., Bertran, Joan, Haque, S. Jaharul, Hentschel, Bettina, Miller, C. Ryan, Furnari, Frank B., Chan, Timothy A., Grosu, Anca-Ligia, Weller, Michael, Barnholtz-Sloan, Jill S., Monje, Michelle, Noushmehr, Houtan, Jenkins, Robert B., Rogers, C. Leland, MacDonald, David R., Pugh, Stephanie L., Chakravarti, Arnab
• Format: Article
• Language: English
• Subjects: Brain Neoplasms - genetics; Child; Epigenome; glioma; Glioma - genetics; Glioma - pathology; H3K27M mutation; haploinsufficiency; Haploinsufficiency - genetics; Humans; IDH mutation; Isocitrate Dehydrogenase; methylome; Mutation - genetics; NF-KappaB Inhibitor alpha - genetics; NFKBIA deletion; nomogram; tumor suppressor
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2023.101082

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas. [Display omitted] •NFKBIA deletions exhibit a distinct pattern relative to other key genetic markers•NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation•NFKBIA deletions engender a transcriptome landscape reminiscent of H3K27M mutant glioma•NFKBIA deletions independently portend poor patient prognosis Bredel et al. characterize multiple adult diffuse glioma populations and reveal that haploinsufficient deletions of NFKBIA portend poor patient prognosis and align with epigenome and transcriptome landscapes that are antithetical to those induced by the IDH mutation and partly reminiscent of those induced by the H3K27M mutation in pediatric gliomas.